Biphenyleneacetic acid anti-inflammatory agents

ABSTRACT

1. A METHOD OF TREATING A CONDITION EXHIBITING AT LEAST ONE OF THE SYMPTOMS OF PAIN, FEVER AND INFLAMMATION WHICH COMPRISES THE ADMINISTRATION TO A PATIENT IN NEED OF SUCH TREATMENT OF A THERAPEUTICALLY EFFECTIVE AMOUNT OF 6-CYANOBIPHENYLENE-2-ACETIC ACID.

Patented Nov. 19, 1974 US. Cl. 424304 4 Claims ABSTRACT OF THEDISCLOSURE Novel biphenyleneacetic acids and derivatives thereof whichare useful in the treatment of inflammation. Also included are processesfor the preparation of the biphenyleneacetic acid materials andtherapeutic compositions and methods of treatment employing said agents.

This application is a continuation-in-part of United States applicationSer. No. 72,531, filed Sept. 15, 1970, now abandoned.

This invention concerns new substituted biphenyleneacetic acids andderivatives and processes for preparing these compounds. A method oftreatment using this novel class of biphenyleneacetic acids as medicinalagents and therapeutic compositions containing said acids is alsodescribed. The compounds of this invention exhibit antiinilammatoryactivity and provide a method of treatment of inflammation. They alsopossess an effective degree of anti-pyretic and analgestic activity.

There has been much research carried on in the past for development ofanti-inflammatory drugs. As a result, a great many new drugs have beensynthesized but most of these have been in the steroid or indole series.

We have unexpectedly found that the substituted biphenyleneacetic acidsof this invention, which are structurally unrelated to the steroid andindole series, are valuable anti-inflammatory agents.

This invention describes new chemical compounds which contain an aceticacid side chain or derivative thereof which is attached to one of thephenyl rings of a biphenylene system.

More specifically, this invention describes a novel class of chemicalcompounds having the structural formula as shown in FIGURE I:

i CI-ICOY FIGURE I Where In the above descriptive portions of thefollowing definitions apply:

Ar or aryl is any benzeneoid or nonbenzenoid aromatic-like structure asphenyl, naphthyl, athracene, styryl, etc.

Alk refers to a hydrocarbon having up to about seven carbon atoms whichmay be straight chained or branched.

Heterocyclo is a radical which may be formed from the nitrogen of anyheterocyclic ring system containing nitrogen and one or more S, O or Natoms and include such as piperidino, morpholino, piperazino,homopiperazino, pyrroledino, indolyl, tetrahydrothiazolyl, etc.

Acyl refers to alkanoyl, aryloyl or aralkanoyl.

Metal refers to any base which will form an acid addition salt with acarboxylic acid and whose pharmacological properties will not cause anadverse physiological effect when ingested by the body system such asalkali, alkaline earth, aluminum metal or any organic cation formed froma positively charged atom or radical such as cyclohexylamine,triethylamine, phenethylamine, etc.

Cycloalk refers to a hydrocarbon ring having up to about seven carbonatoms.

This invention also involves a novel method of treating inflammation andof therapeutic compositions, which comprises the administration to ahuman or animal such as horse, dog, cat, sheep, etc. of a substitutedbiphenyleneacetic acid compound having the structural formula as shownin FIG. I.

The preferred compounds for treating inflammation fever and pain and foruse in therapeutic compositions embrace those compounds of structuralFormula II:

Formula II where R is hydrogen or alkyl;

R is hydrogen, dialkylamino, fluoro, chloro, acetyl, alkyl,

alkoxy or hydroxy;

R is hydrogen, cyano, fluoro, acetyl, chloro, nitro, amino,

dialkylamino, monoalkylamino, alkoxy, mercapto, alkylthio,alkylsulfinyl, trifluoromethyl, alkenyloxy, alkylsulfonyl or hydroxy;

wherein R is at the 6- and/or 7-position. Representative compounds ofthis invention are as follows:

w (4-fluorobiphenylene-2 -propionic acid6,7-dimethoxybiphenylene-Z-acetic acid 6-methoxybiphenylene-2-aceticacid 6,7-difluorobiphenylene-2-acetic acid6-methoxy-7-fluorobiphenylene-Z-acetic acid6-methoxy-7-cyanobiphenylene-2-acetic acid6-trifiu0romethylbiphenylene-2-acetic acid.

In view of the fact that the novel compounds of this invention exerciseanti-inflammatory, analgesic and antipyretic activity they are indicatedfor a wide variety of mammalian conditions where one or more of thesymptoms of inflammation, fever and pain are manifested. Exemplary ofsuch conditions are rheumatic diseases for example, rheumatoidarthritis, osteoarthritis, and other degenerative joint diseases,psoriatic arthritis, ankylosing spondylitis, gout and rheumatic fever;soft tissue rheumatism, for example, tendinitis, periarthritis andperiostitis; acute muscular rheumatism, for example sciatica and thelike; treatment of pain after fractures, pain and inflammationassociated with dental surgery, and the like, human and veterinarydisease conditions exhibiting the foregoing symptoms requiring the useof an anti-inflammatory, analgesic and/ or anti-pyretic pharmaceuticalcomposition.

The compounds of this invention may be in a form suitable for oral use,for example, as tablets, aqueous or oil suspensions, dispersible powdersor granules, emulsions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide apharmaceutically elegant and palatable preparation. Tablets whichcontain the active biphenyleneacetic acids ingredient in admixture withnon-toxic pharmaceutically acceptable excipients are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, for example, calcium carbonate, sodium carbonate, lactose,calcium phosphate or sodium phosphate; granulating and disintegratingagents, for example, maize starch or alginic acid; binding agents, forexample, starch, gelatin or acacia; and lubricating agents, for example,magnesium stearate, steric acid or tale. The tablets may be uncoated orthey may be coated by known techniques to delay disintegration andabsorption in the gastro-intestinal tract and thereby provide asustained action over a longer period.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient'is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with an oilmedium, for example, arachis oil, liquid paraffin or olive oil.

Aqueous solutions containing the active biphenyleneacetic acids form afurther embodiment of this invention. Excipients suitable for aqueoussuspensions may be employed if desired. These excipients are suspendingagents, for example, sodium carboxymethylcellulose, methyl cellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gumtragacanth and gum acacia; dispersing or wetting agents may be anaturallyoccurring phosphatide, for example, lecithin; or condensationproducts of an alkylene oxide with fatty acids, for example,polyoxyethylene stearate; or condensation products of ethylene oxidewith long-chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol; or condensation products of ethylene oxide with partial estersderived from fatty acids and a hexitol, for example, polyoxyethylenesorbitol monooleate; or condensation products of ethylene oxide withpartial esters derived from fatty acids and hexitol anhydrides, forexample, polyoxyethylene sorbitan monooleate. The said aqueoussuspensions may also contain one or more preservatives, for example,

ethyl, or n-propyl, p-hydroxy benzoate, one or more coloring agents, oneor more flavoring agents, and one or more sweetening agents, such assucrose.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example, arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil, such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example, beeswax, hardparafiin or cetyl alcohol. Sweetening agents, such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuepension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, flavoring and coloringagents may also be present.

The compounds of this invention may also be in the form of oil-in-wateremulsions. The oily phase may be a vegetable oil, for example, olive oilor arachis oils, or a mineral oil, for example, liquid paraflin ormixtures of these. Suitable emulsifying agents may be naturallyoccurringgums, for example, gum acacia or gum tragacanth, naturally-occurringphosphatides, for example, soya bean lecithin, and esters of partialesters derived from fatty acids and hexitol anhydrides, for example,sorbitan monooleate, and condensation products of the said partialesters with ethylene oxide, for example, polyoxyethylene sorbitanmono-oleate. The emulsions may also contain sweetening and flavoringagents.

Syrups and elixirs may be formulated with sweetening agents, forexample, glycerol, sorbitol or sucrose. Such formulations may alsocontain a demulcent, a preservative and flavoring and coloring agents.The pharmaceutical compositions may be in the form of a sterileinjectable preparation, for example, as a sterile injectable aqueoussuspension. This suspension may be formulated according to the known artusing those suitable dispersing or wetting agents and suspending agentswhich have been metioned above. The sterile injectable preparation mayalso be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example, as a solutionin 1:3-butane diol.

The biphenyleneacetic acids of this invention may also be administeredin the form of suppositories for rectal administration of the drug.These can be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures, but liquid at therectal temperature and will therefore melt in the rectum to re lease thedrug. Such materials are cocoa butter and polyethylene glycols.

Further, these compounds may be tableted or otherwise formulated so thatfor every 100 parts by weight of the composition, there are presentbetween 5 and 95 parts by weight of the active ingredient, andpreferably between 25 and parts by weight of the active ingredient. Thedosage unit form will generally contain between about 50 mg. and about500 mg. of the active ingredient of the formula stated above.

From the foregoing formulation discussion, it is apparent that thecompounds of this invention can be administered orally, parenterally,topically and rectally. The term parenteral as used herein includessubcutaneous injection, intravenous, intramuscular, or intrasternalinjection or infusion techniques.

The dosage regimen in carrying out the methods of this invention is thatwhich insures maximum therapeutic response until improvement is obtainedand thereafter is the minimum eflective level which gives relief. Thus,in general, the dosages are those that are therapeutically effective inthe treatment of disease conditions or symptoms, such as inflammation,pain and fever. In general, the daily oral dose for an animal or humanis between about 0.5 mg./kg. and 70 mg./kg., bearing in mind, of course,that in selecting the appropriate dosage in any specific case,consideration must be given to the patients weight, general health, ageand other factors which may influence response to the drug. A typicaldosage for an adult human would involve 36 capsules a day at mealtimes,each capsule containing 50 mg. of the active ingredient.

It is expected that the biphenyleneacetic acids of this invention willgenerally be administered in dosage units of between 5 and 500 mg. ofactive ingredient. Preferred compositions for ease of administration arein oral dosage unit form, for example, tablets or capsules, containingbetween 25 and 250 mg. of the biphenyleneacetic acids of this invention.

The compounds of this invention may be conveniently prepared by thefollowing general method. When a substituted acetylbiphenylene compoundis subjected to the conditions of the Wilhgerodt-Kindler reactionfollowed by hydrolysis then the desired substituted biphenyleneaceticacid product is prepared. If the ketone is heated with an equimolaramount of sulfur and an anhydrous amine the thioamide is formed whichcan then be hydrolyzed in the usual manner to the acid. The amine usedmay be one which is a primary or a secondary amine of the formula HNRR"where R and R" may be the same or different and may be alkyl, alkenyl,aralkyl, aryl, or a heterocyclic chain which will form an amine ringsuch as piperidine, morpholine, etc. This reaction is described by thefollowing reaction sequence:

The 2-substituted biphenyleneacetic acid compounds may further beprepared by the hydrolysis of the corresponding nitrile in the usualmanner. This is described by the following reaction equation:

R R (EHCN CHAJOOH One such method of hydrolysis is by heating in acidsolualternatively, the biphenyleneacetic acid may be converted to itsacid halide by conventional methods and the acid halide thus formedreacted with an appropriate alkanol ar aralkanol. The methyl ester isobtained employing diazomethane.

The compounds of this invention, wherein Y is a group such that an amideis the final compound (i.e., Y is amino), may be prepared by anysuitable amidation reaction. For example, the acid compound (preferablythe methyl or ethyl ester) may be reacted with ammonia, ammoniumhydroxide, or an amine compound, at any suitable temperature (roomtemperature to reflux). When the amino group is desired, it is preferredto carry out the reaction with ammonia in a bomb at temperatures aboveC. to form the desired Y (amino) compound. Preferably, when an amide isdesired which is derived from an amino acid, the following reactionsequence is followed: The benzoic acid final compound is reacted withisobutyl chloroformate to form the mixed anhydride. This compound is inturn reacted with the desired amino acid ester and subsequentlyhydrolyzed to form the desired amide.

Appropriately desired end products having various R, R and Rsubstituents can be prepared using suitable reactions in order toconvert one group to another. Thus, for example, using conventionalmethods a halogen group can be converted under normal conditions to thenitrile compound which in turn can be hydrolyzed to a carboxy. Formationof the acid halide followed by alkylation affords the alkanoyl groups. Anitro can be reduced to an amino group and a hydroxy compound can beprepared by demethylation of a methoxy substituent. Mercapto groups canbe converted into alkylthio or arylthio groups using conventionalmethods and can further be oxidized to the sulfinyl and sulfonylcompounds. Examples of the substituted biphenylene-acetic and propionicacids which may be made from other acids of the invention viadisplacement, addition, etc. reactions are as follows: Treatment ofmethyl 6-bromo (or chloro) biphenyIene-Z-acetate with cuprous cyanide inN-methylpyrrolidine yields the corresponding 6-cyano derivative.Reaction of methyl 6-carboxybiphenylene-Z-acetate with sulfurtetrafiuoride yields the 6-trifluoromethyl analog. Oxidation of6-methylthiobiphenyIene Z-acetic acid with sodium metaperiodate inacetone-water yields the 6-methylsulfinyl derivative. Alkylation of thehydroxy and amino derivatives yields the corresponding alkoxy andalkylamino analogs.

This invention further relates to the acid addition salts found by theaction of a suitable base with a carboxylic acid. Suitable bases thusinclude, for example, the alkali metal alkoxide such as sodiummethoxide, etc. and the alkali metal and alkaline earth metalhydroxides, carbonates, bicarbonates etc. (such as sodium hydroxide,potassium hydroxide, calcium hydroxide, potassium carbonate, magnesiumbicarbonate, etc.). Also, the aluminum salts of the instant products maybe obtained by treating the corresponding sodium salt with anappropriate aluminum complex such as aluminum chloride hexahydrate, etc.

Representative salts, esters and amides are as follows:

methyl biphenylene-2-acetate ethyl a-(Z-biphenylene)-propionate propylbiphenylene-l-acetate t-butyl oc-( l-biphenylene)-propionate methyl3-methoxybiphenylene-2-acetate propyl 3-hydroxybiphenylene-Z-acetateN-methyl 3-methylbiphenylene-Q-acetamide N-ethyl6-acetylbiphenylene-2acetamide N,N-dimethyl3,6-dimethoxybiphenylene-2-acetamide3,6-dihydroxybiphenylene-2-acetmorpholide sodium6-hydroxybiphenylene-Z-acetate potassium 6-nitrobiphenylene-Z-acetatecalcium 6-dimethylaminobiphenylene-2-acetate sodium6-mercaptobiphenylene-Z-acetate aluminum6-methylthiobiphenylene-Z-acetate phenyl6-methylsulfinylbiphenylene-2-acetate benzyl6-cyanobiphenylene-Z-acetate phenethyl3-hydroxy-6-methylsulfinylbiphenylene-Z- acetate 6-(methylamino)biphenylene-Z-acetpiperazide methyl ot-(3-methyl-2-biphenylenyl) pionatesodium a-(3-methoxy-2-biphenylenyl) propionate N,N-diethyla-(3-chloro-2-biphenylenyl) propionamide ethyla-(3-bromo-2-biphenylenyl) propionate a-(3-amino-2-biphenylenyl)propionamide N-methyl a-(3-dimethylamino-Z-biphenylenyl) propionamidepropyl tx-(3-mercapto-2-biphenylenyl) propionatea-(3methylthio-2-biphenylenyl) propiomorpholide calciumot-(3-phenyl-2-biphenylenyl) propionate benzyla-(3-benzyl-2-biphenylenyl) propionate n-butyla-(3,6-dimethoxy-2-biphenylenyl) propionate ethyla-(3,6-dihydroxy-2-biphenylenyl) propionate potassiuma-(3,6-dichloro-2-biphenylenyl) propionate phenethyla-(6-methoxy-2-biphenylenyl) propionate EXAMPLE 1 Biphenylene-2-aceticacid A mixture of Z-acetylbiphenylene (2.0 g., 0.015 m.), sulfur (0.85g.) and dried morpholine (7 ml.) is refluxed under a nitrogen atmospherefor 24 hours, allowed to cool, added to 105 m1. of an aqueous potassiumhydroxide solution (from 27 g. potassium hydroxide in 128 ml. water),transferring with a small amount of fresh morpholine, the aqueousmixture filtered hot, and the cake washed with additional water. Thefiltrate is then ice-cooled, acidified slightly with concentratedhydrochloric acid, keeping the temperature of the mixture below 14 C. byexternal cooling and addition of small amounts of ice to the solution.After stirring several hours, the mixture is re-cooled to 5 C.,filtered, the crude product washed well with water, dried, boiled twicewith excess methylene chloride, the extracts filtered and concentratedto 1.7 g. of biphenylene- 2-acetic acid, LR. identical to analyticalmaterial, mp. 168174 C. (Benzene).

When the compounds of Table I below are substituted forZ-acetylbiphenylene in the above example, then the corresponding productof Table II below is obtained.

TABLE I 2-acetyl-3 -methylbiphenylene 2-acetyl-3-methoxybipheny1ene2-acetyl-3-chlorobiphenylene 2-acetyl-3-bromobiphenylene2-acetyl-6-fluorobiphenylene Z-acetyl-6-trifluoromethylbiphenyleneZ-acetyl-3-dimethylaminobiphenylene 2-acetyl-3-methylthiobipheny1ene2-acetyl-6-phenylbiphenylene 2-acetyl-6-benzylbiphenylene2-acetyl-3,G-dimethoxybiphenylene 2-acetyl-3,6-dihydroxybiphenylene2-acetyl-3,6-dichlorobiphenylene 2-acetyl-6-methoxybipheny1ene TABLE II3-methylbiphenylene-2-acetic acid 3-methoxybiphenylene-2-acetic acid3-chlorobiphenylene-Z-acetic acid 3-bromobiphenylene-2-acetic acid6-fluorobiphenylene-2-acetic acid 6-trifiuoromethylbiphenylene-2-aceticacid 3-dimethylaminobiphenylene-Z-acetic acid3-methylthiobiphenylene-2-acetic acid 6-phenylbiphenylene-Z-acetic acid6-benzylbiphenylene-Z-acetic acid 3,6-dimethoxybiphenylene-2-acetic acid3,6-dihydroxybiphenylene-2-acetic acid 3,6-dichlorobiphenylene-2-aceticacid 6-methoxybiphenylene-Z-acetic acid 8 EXAMPLE 2 2- a-Hydroxyethyl-biphenylene To an ice-cooled suspension of Z-acetylbiphenylene (1.0 g.,0.005 m.) in ethanol (ca. 40 ml.) is added a partial solution of sodiumborohydride (0.2 g.) in ethanol (5 ml.)-water (0.5 ml.) over about 1minute. Upon allowing the mixture to warm to room temperature, solutionoccurs. After stirring overnight, water (50 ml.) is added, the mixturestirred an additional 3 hrs., the ethanol removed in vacuo (roomtemperature), filtered, the solid washed with water and dried to give2-(a-hydroxyethy1)- biphenylene.

When the compounds of Table II, Example 1 are substituted in the aboveexample for 2-acetylbiphenylene, then the products prepared as shown inTable III below:

TABLE III 2- a-Hydroxyethyl) -3 -methylbiphenylene 2- u-Hydroxyethyl) -3-methoxybiphenylene 2- a-Hydroxyethyl) -3 -chlorobiphenylene 2-a-Hydroxyethyl -3 -bromobiphenylene 2- a-Hydroxyethyl-6-fluorobiphenylene 2- a-Hydroxyethyl) -6-trifluoromethylbiphenylene 2-(a-Hydroxyethyl -3 -dimethylaminobiphenylene 2- a-Hydroxyethyl) -3-methylthiobiphenylene 2- (a-Hydroxyethyl -6-phenylbiphenylene 2-a-Hydroxyethyl) -6-benzylbiphenylene 2- wHydroxyethyl) -3,6-dirnethoxybiphenylene 2- a-Hydroxyethyl) -3,6-dihydroxybiphenylene 2-a-Hydroxyethyl -3 6-dich1orobiphenylene 2- a-Hydroxyethyl)-6-methoxybiphenylene EXAMPLE 3 2- a-Bromoethyl) -biphenylene To awell-stirred partial solution of 2-(a-hydroxyethyl)- biphenylene (1.0g.) in dry benzene (15 ml.) at 5 C. is added gaseous hydrogen bromide,the bubbling in at such a rate as to keep the temperature less than 11C. After ca. ten minutes, hydrogen bromide vapor is visible at the mouthof the drierite exit tube protecting the mixture. The rate of additionis increased and addition continued for an additional 35 min., keepingthe temperature between 38 C. The green mixture is then transferred to aseparatory funnel, the benzene solution separated from the water formedduring the reaction, dried over anhydrous sodium sulfate-darco(stirring), filtered and concentrated in vacuo (bath temperature nogreater than 40 C.) to a yellow wax, which after pumping all night atroom temperature weighs 1+ g. The crude 2-(a-bromoethyl)-biphenylene isused as-is in the following example.

When the compounds of Table III, Example 2 are substituted in the aboveexample for 2-(a-hydroxyethyl)- biphenylene then the products preparedare shown in Table IV below:

TABLE IV EXAMPLE 4 oc- 2-Bisphenylenyl) -propionitrile To a stirredmixture of sodium cyanide (0.4 g.) in dry dimethylsulfoxide (5 ml.) at64 C. (bath temperature) is added 2-(ot-bromoethyl)-biphenylene (1.0 g.)in small portions over one hour. After all is added, the bath is raisedto 77:2 C. and the mixture kept one hour. After cooling, water is addedand the fluid mixture extracted well with methylene chloride. Theorganic phase is then Washed, three times with Water, dried overmagnesium sulfate darco, filtered, and concentrated to a deep yellowredoil of ot(2-biphenylenyl)-propionitrile.

When the compounds of Table IV, Example 3 are substituted in Example 4for 2-(wbromoethyl)biphenylene, then the products prepared are shown inTable V.

TABLE V 2- 3-methyl-2-biphenylenyl) -propionitrile 2-3-bromo-2-biphenylenyl) -propionitrile 2- (3-chloro-2-biphenylenyl)-propionitrile 2- 6-fluoro-2-biphenylenyl) -propionitrile 1-6-trifluoromethyl-2-biphenylenyl -propionitrile 2-3-dimethylamino-2-biphenylenyl -propionitrile 2-3-methylthio-2-biphenylenyl -pr0pionitrile 2- 6-phenyl-Z-biphenylenyl)-propionitrile 2- 6-benzyl-2-biphenylenyl) -propionitrile 2- 3,6-dimethoxy-Z-biphenylenyl) -propi0nitrile 2-3,6-dihydroxy-2-biphenylenyl -propionitrile 2- 3,6-dichloro-Z-biphenylenyl) -propionitrile 2- (6-mcthoxybiphenyleny1)-propionitrile EXAMPLE a-(Z-Biphenylenyl)-propionic acid A mixture ofu-(l-biphenyenyl)-propionitrile (0.01 m.), glacial acetic acid (50 ml.),sulfuric acid (10 ml.) and water (10 ml.) is heated under reflux forhours, cooled and distributed carefully between ether-saturatedbicarbonate solution. The aqueous layer is then Washed with ether,acidified, extracted with chloroform and the chloroform removed. Theresidue is recrystallized from hexane to yielda-(Z-biphenylenyl)-propi0nic acid, m.p. 135-138 C.

When the compounds of Table V, Example 4 are used in place of thenitrile in the above example, then the corresponding products of TableVI below are obtained:

TABLE VI ot- (3-methyl-2-biphenylenyl) -propionic acida-(3-methoxy-2-biphenylenyl)-propionic acid a- 3-chloro-2-biphenylenyl)-propionic acid Ml a- 3-bromo-2-biphenylenyl) -propionic acid u-3-amino-2-biphenylenyl) -propionic acid 02-3-dimethylamino-2-biphenylenyl) -propionic acid OL-3-mercapto-2-biphenylenyl -propionic acid zx- (3-methylthio-2-biphenylenyl -propionic acid w 3-phenyl-2-biphenylenyl-propionic acid ot- 3-benzyl-2-biphenylenyl) -propionic acid w (3,6-dimethoxy-Z-biphenylenyl) --propionic acid oc-3,6-dihydroxy-Z-biphenylenyl) -propionic acid rx- (3,6-dichloro-2-biphenylenyl) -propionic acid ot-6-methoxy-2-biphenylenyl) -propionic aicd w S-fluoro-Z-biphenylenyl)-propionic acid it- 6fiuoro-2-biphenylenyl) -propionic acid 11-6-methylthio-2-biphenyleny1) -propionic acid (6- 6-methylsuh'inyl)-2-biphenylenyl) -propionic acid.

We claim:

1. A method of treating a condition exhibiting at least one of thesymptoms of pain, fever and inflammation which comprises theadministration to a patient in need of such treatment of atherapeutically effective amount of 6-cyanobiphenylene-Z-acetic acid.

2. A method of treating a condition exhibiting at least one of thesymptoms of pain, fever, and inflammation which comprises theadministration to a patient in need of such treatment of atherapeutically effective amount of 3-chlorobiphenylene-2-acetic acid.

3. A method of treating a condition exhibiting at least one of thesymptoms of pain, fever and inflammation which comprises theadministration to a patient in need of such treatment of atherapeutically effective amount of 6-fiuorobiphenylenc-2-acetic acid.

4. A method of treating a condition exhibiting at least one of thesymptoms of pain, fever and inflammation which comprises theadministration to a patient in need of such treatment of atherapeutically effective amount of 6-methoxybiphenylene-Z-acetic acid.

References Cited Chem. Abst., vol. 57, Subject Index A-I, p. 3965(1962). Chem. Abst., vol. 68, 59353 Z (1968).

STANLEY J. FRIEDMAN, Primary Examiner US. Cl. X.R.

1. A METHOD OF TREATING A CONDITION EXHIBITING AT LEAST ONE OF THESYMPTOMS OF PAIN, FEVER AND INFLAMMATION WHICH COMPRISES THEADMINISTRATION TO A PATIENT IN NEED OF SUCH TREATMENT OF ATHERAPEUTICALLY EFFECTIVE AMOUNT OF 6-CYANOBIPHENYLENE-2-ACETIC ACID.